The parent grant of this supplement application is focused on testing the mechanistic hypothesis that oligodendrocyte and myelin related (OMR) gene and protein expression deficits in schizophrenia (SZ) are due, at least in part, to abnormalities in the execution of the cell-cycle program by oligodendrocytes. However, despite considerable theoretical and translational interest in the developmental hypothesis of schizophrenia and the known close temporal relationship between myelination and the age of onset of SZ, the parent grant was not designed or resourced to address the fundamental question of whether the OMR and cell cycle abnormalities in schizophrenia arise from developmental challenges or influences. Similarly, although the parent grant goes to considerable lengths to minimize the potential influence of antipsychotic treatment on the results from studies of persons with SZ, it does not attempt to determine the influence, beneficial or detrimental, of antipsychotic medication on the observed OMR and cell-cycle abnormalities directly. Published results from us and others suggest that antipsychotic agents can influence OMR gene expression, but the direction of effect is unclear and how these pharmacological agents affect the execution of the OMR associated cell cycle programs is unknown. Thus, it is not known how age and developmental state modulate OMR gene and protein expression and whether oligodendrocytes are more or less vulnerable to stress within their microenvironment at different postnatal ages. Similarly, it is not clear whether and how the OMR and cell cycle related (CCR) gene and protein expression abnormalities noted in SZ are influenced by antipsychotic medications. The studies proposed in this Supplemental/Revision application are intended to extend the concepts developed in the parent application to address these questions using a well-established animal model of myelin damage and recovery. Mice will be treated with cuprizone for 4 weeks at different ages and the OMR and CCR processes affected by demyelination and remyelination will be studies by quantitative gene and protein expression assays in cortical grey and white matter. Similar procedures will be employed to study the beneficial and/or detrimental effects of typical and atypical antipsychotic agents on OMR and CCR gene and protein expression during demyelination and remyelination. Scientifically, the proposed studies represent an extension of those in the parent grant with direct relevance to the analysis and understanding of the role of myelin, oligodendrocytes and cell-cycle processes in schizophrenia. At the same time, the proposed studies are responsive and faithful to the NIMH topic areas of interest, addressing the "Translational Science" and the "Understanding Postnatal Brain Development" and "critical periods" requirements of the RFA (NOT-OD-09- 058). In addition, this application is responsive to the ARRA in that it will employ two BA-level scientists and ensure the continued employment of a Ph.D. scientist. Furthermore, the award of this application will result in the indirect additional employment of one animal care technician. PUBLIC HEALTH RELEVANCE: Recently, genetic, neuroimaging and postmortem neurobiology studies from multiple laboratories have consistently found abnormalities associated with myelination in the brain of persons with schizophrenia. The parent grant of this supplement application is investigating gene and protein expression changes in specific populations of neurons and oligodendrocytes in postmortem tissue from persons with schizophrenia. How myelin associated gene and protein deficits are affected by age and development and how antipsychotic drugs affect demyelination and remyelination is not addressed by the parent grant. The current proposal aims to address both these questions using an animal model system.